ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling
| Autor: | Kate G. R. Quinlan, Paul Gregorevic, Jane T. Seto, Fleur C. Garton, Peter J. Houweling, Nigel Turner, Marshall W. Hogarth, Daniel G. MacArthur, Monkol Lek, Nan Yang, Gregory J. Cooney, Xi Fiona Zheng, Kathryn N. North |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Mice 129 Strain Genotype Population Muscle Proteins macromolecular substances Actinin Biology Binding Competitive Mice Filamin binding Endurance training Physical Conditioning Animal Chlorocebus aethiops medicine Animals Humans Calcium Signaling Muscle Strength Muscle Skeletal education Genetic Association Studies Aged Calcium signaling Mice Knockout Genetics education.field_of_study Calcineurin Actinin binding Microfilament Proteins Skeletal muscle General Medicine Middle Aged Adaptation Physiological Cell biology Mice Inbred C57BL medicine.anatomical_structure COS Cells Physical Endurance Female Carrier Proteins Protein Binding Research Article |
| Zdroj: | Journal of Clinical Investigation. 123:4255-4263 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci67691 |
| Popis: | α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to “slowing” of the metabolic and physiological properties of fast fibers. Here, we have shown that α-actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-actinin-3–deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-actinins play a role in the regulation of calcineurin signaling. |
| Databáze: | OpenAIRE |
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